title: Uptake of catamphiphilic drugs into erythrocytes and muscular tissue correlates to membrane enrichment and to 45Ca displacement from phosphatidylserine monolayers.
abstract: The uptake of the catamphiphilic drugs flunarizine, R 56865 [N-1-4-(4-fluorophenoxy)butyl-4-piperidinyl-N-methyl-2- benzothiazolamine], verapamil, diltiazem, lidocaine and the noncatamphiphilic drug nitrendipine into erythrocytes and erythrocyte membranes was measured at pH 7.2 in a Ringer's solution at 22 degrees C. The uptake was concentration proportional between 10(-8) and 10(-6) mol/l for all drugs investigated; the erythrocyte/medium ratio (E/M) was constant after 20 min in all experiments. In rat aortas and left atria drug uptake was measured in a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffered medium (pH 7.2, 32 degrees C). Equilibrium was reached after 360 min and the tissue/medium ratio (T/M) was concentration proportional between 10(-8) and 10(-6) mol/l for all drugs. E/M or T/M ratios, respectively, increased in the order: erythrocytes less than aortas less than left atria. However, the particular drug/phospholipid ratios were relatively constant for the drugs investigated, indicating that the membranes were a major distribution phase for these drugs. For the catamphiphilic drugs, the E/M or T/M ratios correlated linearly with the EC50 for 45Ca displacement from phosphatidylserine monolayers, but were poorly correlated with the octanol-water coefficient of the unchanged molecules. The EC50 for 45Ca displacement from phosphatidylserine monolayers is a measure for the uptake of the protonated species of catamphiphilic drugs into erythrocytes or tissue and may be a good estimate of tissue uptake of these drugs in general.
authors.affiliation: Janssen Research Foundation, Neuss, FRG.
authors.forename: E
authors.initials: E
authors.lastname: Scheufler
authors.forename: R
authors.initials: R
authors.lastname: Vogelgesang
authors.forename: B
authors.initials: B
authors.lastname: Wilffert
authors.forename: B L
authors.initials: BL
authors.lastname: Pegram
authors.forename: J B
authors.initials: JB
authors.lastname: Hunter
authors.forename: D
authors.initials: D
authors.lastname: Wermelskirchen
authors.forename: T
authors.initials: T
authors.lastname: Peters
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004110:Diltiazem / Q000493:pharmacokinetics; D004912:Erythrocytes / Q000378:metabolism*; D005444:Flunarizine / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008012:Lidocaine / Q000493:pharmacokinetics; D009132:Muscles / Q000378:metabolism*; D009568:Nitrendipine / Q000493:pharmacokinetics; D010718:Phosphatidylserines / Q000378:metabolism*; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D010718:Phosphatidylserines; D008012:Lidocaine; D009568:Nitrendipine; D014700:Verapamil; D004110:Diltiazem; D005444:Flunarizine; D002118:Calcium